APRANK: Computational Prioritization of Antigenic Proteins and Peptides From Complete Pathogen Proteomes.

Availability of highly parallelized immunoassays has renewed interest in the discovery of serology biomarkers for infectious diseases. Protein and peptide microarrays now provide a rapid, high-throughput platform for immunological testing and validation of potential antigens and B-cell epitopes. However, there is still a need for tools to prioritize and select relevant probes when designing these arrays. In this work we describe a computational method called APRANK (Antigenic Protein and Peptide Ranker) which integrates multiple molecular features to prioritize potentially antigenic proteins and peptides in a given pathogen proteome. These features include subcellular localization, presence of repetitive motifs, natively disordered regions, secondary structure, transmembrane spans and predicted interaction with the immune system. We trained and tested this method with a number of bacteria and protozoa causing human diseases: Borrelia burgdorferi (Lyme disease), Brucella melitensis (Brucellosis), Coxiella burnetii (Q fever), Escherichia coli (Gastroenteritis), Francisella tularensis (Tularemia), Leishmania braziliensis (Leishmaniasis), Leptospira interrogans (Leptospirosis), Mycobacterium leprae (Leprae), Mycobacterium tuberculosis (Tuberculosis), Plasmodium falciparum (Malaria), Porphyromonas gingivalis (Periodontal disease), Staphylococcus aureus (Bacteremia), Streptococcus pyogenes (Group A Streptococcal infections), Toxoplasma gondii (Toxoplasmosis) and Trypanosoma cruzi (Chagas Disease). We have evaluated this integrative method using non-parametric ROC-curves and made an unbiased validation using Onchocerca volvulus as an independent data set. We found that APRANK is successful in predicting antigenicity for all pathogen species tested, facilitating the production of antigen-enriched protein subsets. We make APRANK available to facilitate the identification of novel diagnostic antigens in infectious diseases.

Lrrk2 alleles modulate inflammation during microbial infection of mice in a sex-dependent manner.

Variants in the leucine-rich repeat kinase-2 (LRRK2) gene are associated with Parkinson's disease, leprosy, and Crohn's disease, three disorders with inflammation as an important component. Because of its high expression in granulocytes and CD68-positive cells, LRRK2 may have a function in innate immunity. We tested this hypothesis in two ways. First, adult mice were intravenously inoculated with Salmonella typhimurium, resulting in sepsis. Second, newborn mouse pups were intranasally infected with reovirus (serotype 3 Dearing), which induced encephalitis. In both mouse models, wild-type Lrrk2 expression was protective and showed a sex effect, with female Lrrk2-deficient animals not controlling infection as well as males. Mice expressing Lrrk2 carrying the Parkinson's disease-linked p.G2019S mutation controlled infection better, with reduced bacterial growth and longer animal survival during sepsis. This gain-of-function effect conferred by the p.G2019S mutation was mediated by myeloid cells and was abolished in animals expressing a kinase-dead Lrrk2 variant, p.D1994S. Mouse pups with reovirus-induced encephalitis that expressed the p.G2019S Lrrk2 mutation showed increased mortality despite lower viral titers. The p.G2019S mutant Lrrk2 augmented immune cell chemotaxis and generated more reactive oxygen species during virulent infection. Reovirus-infected brains from mice expressing the p.G2019S mutant Lrrk2 contained higher concentrations of α-synuclein. Animals expressing one or two p.D1994S Lrrk2 alleles showed lower mortality from reovirus-induced encephalitis. Thus, Lrrk2 alleles may alter the course of microbial infections by modulating inflammation, and this may be dependent on the sex and genotype of the host as well as the type of pathogen.

The molecular genetics of inflammatory, autoimmune, and infectious diseases of the sinonasal tract: a review.

CONTEXT: The sinonasal tract is frequently affected by a variety of nonneoplastic inflammatory disease processes that are often multifactorial in their etiology but commonly have a molecular genetic component. OBJECTIVE: To review the molecular genetics of a variety of nonneoplastic inflammatory diseases of the sinonasal tract. DATA SOURCES: Inflammatory lesions of the sinonasal tract can be divided into 3 main categories: (1) chronic rhinosinusitis, (2) infectious diseases, and (3) autoimmune diseases/vasculitides. The molecular diagnosis and pathways of a variety of these inflammatory lesions are currently being elucidated and will shed light on disease pathogenesis and treatment. CONCLUSIONS: The sinonasal tract is frequently affected by inflammatory lesions that arise through complex interactions of environmental, infectious, and genetic factors. Because these lesions are all inflammatory in nature, the molecular pathology surrounding them is most commonly due to upregulation and down-regulation of genes that affect inflammatory responses and immune regulation.

Micronutrients influencing the immune response in leprosy / Micronutrientes que influyen en la respuesta immune en la lepra

La lepra es una enfermedad infecciosa crónica causada por el Mycobacterium leprae, un bacilo intracelular de transmisión aérea. La enfermedad afecta la piel y los nervios periféricos y causa secuelas neurológicas. El bacilo se multiplica lentamente en el hospedador y posiblemente la enfermedad ocurre por el mal funcionamiento de la respuesta inmunitaria del hospedador. Esta revisión aborda el papel de algunos micronutrientes específicos en la respuesta inmunitaria, tales como las vitaminas A, D, E, C, el cinc y el selenio, detallando sus mecanismos de acción en las enfermedades infecciosas y en la lepra. La respuesta inmunitaria a los patógenos libera sustancias nocivas que producen lesión tisular. Esta revisión también aborda cómo una menor cantidad de antioxidantes puede contribuir a un aumento del estrés oxidativo y a complicaciones de las enfermedades infecciosas y la lepra. Puesto que los micronutrientes poseen un efecto regulador de la respuesta inmunitaria innata y adaptativa, es importante un equilibrio perfecto de sus concentraciones para mejorar la respuesta inmunitaria frente a los patógenos (AU)

Leprosy is a chronic infectious disease caused by Mycobacterium leprae, an intracellular bacillus of airborne transmission. The disease affects the skin and peripheral nerves and can cause neurological sequelae. The bacillusmultiplies slowly in the host and the disease probably occurs due to malfunctioning in host immune response. This review addresses the role of some specific micronutrients in the immune response, such as Vitamins A, D, E, C, Zinc and Selenium, detailing their mechanisms of actions in infectious diseases, and in leprosy. The immune response to pathogens releases harmful substances, which lead to tissue damage. This review discusses how a decreased level of antioxidants may contribute to an increased oxidative stress and complications of infectious diseases and leprosy. As the nutrients have a regulatory effect in the innate and adaptative immune responses, a perfect balance in their concentrations is important to improve the immune response against the pathogens (AU)

The gene-immune-behavioral pathway: Gamma-interferon (IFN-γ) simultaneously coordinates susceptibility to infectious disease and harm avoidance behaviors.

Cytokine gene variants are known to influence both infectious disease susceptibility and harm-avoidant behaviors, suggesting that these risk variants may be pleiotropically linked to instinctual disease-avoidant traits. The gamma-interferon (IFNG) +874 T>A polymorphism (rs2430561) is an ideal candidate gene variant for immune-behavioral studies. It is a functional SNP, regulating IFNG mRNA expression; it is known to modulate serotonergic activity and is therefore capable of modifying behavior; and it has previously been associated with increased susceptibility to malaria, tuberculosis, leprosy and Chagas disease. We hypothesized that the infectious disease-high-risk IFNG +874 A-allele would be associated with four personality traits previously reported as behavioral defenses against infection: Harm Avoidance (HA), Extraversion (E), Exploratory Excitability (Exp E), and Openness to Experience (O). We tested this hypothesis in a sample of 168 healthy university students from Southern California genotyped for IFNG +874 T>A and evaluated by the Temperament and Character Inventory-Revised (TCI-R) and the NEO Five-Factor Inventory (NEO-FFI). We found that the infectious disease-high-risk IFNG +874 A-allele was associated with increased HA (P=0.001) and decreased E (P=0.030) and Exp E (P=0.030). These findings suggest that the IFNG +874 A gene variant is linked both to infectious disease susceptibility and to proactive behavioral defenses that reduce infection risk in healthy subjects.

[What it means to be "infected"--how a human body, or health professionals combat "infection"].

Human immunology and relationship between immune mechanism and infection were explained. Humoral immunity and cellular immunity collaborate properly and eliminate microorganisms. In immunocompromised host these mechanisms are broken. For prevention of healthcare associated infections, standard precausion is important basically. Additionary, according to the status of the patient, contact precaution, droplet precaution or airborne precaution should be applied.

Antiphospholipid antibodies, antiphospholipid syndrome and infections.

Since the association between antiphospholipid antibodies (aPL) and syphilis was first described, many other viral, bacterial and parasitic infections have been shown to induce antiphospholipid antibodies, notably anticardiolipin antibodies (aCL). A review of the literature shows that while aCL occur frequently in viral infections, particularly in HIV (49.75%), HBV (24%) and HCV (20%), it is very rarely associated with anti-beta2 glycoprotein I antibodies (anti-beta2GPI) and is not correlated with thrombosis risk or hematological manifestations of the antiphospholipid syndrome (APS). Concerning bacterial infections, aCL is often present in leprosy (42.7%), where it is frequently associated with the presence of anti-beta2GPI (44.8%), and in syphilis infections (8 to 67%), though without correlation with thrombotic events. Though few individual patients with unequivocal infection-induced aPL satisfy criteria for APS, the lack of statistical association with thrombotic events strongly argues against the identification of a true APS subset in this context. However, physicians should keep in mind the fact that an infection, generally bacterial, in patients with confirmed APS, may lead to catastrophic antiphospholipid syndrome with a possible fatal outcome.

The Nramp1 protein and its role in resistance to infection and macrophage function.

Susceptibility to infectious diseases is under genetic control in humans. Animal models provide an ideal tool to study the genetic component of susceptibility and to identify candidate genes that can then be tested for association or linkage studies in human populations from endemic areas of disease. The Nramp1 gene was isolated by positional cloning the host resistance locus Bcg/Ity/Lsh, and mutations at this locus impair the resistance of mice to infections with intracellular parasites, such as Salmonella, Leishmania, and Mycobacterium. Allelic variants at the human Nramp1 homologue have recently been found to be associated with susceptibility to tuberculosis and leprosy in humans. The Nramp1 protein is an integral membrane protein expressed exclusively in the lysosomal compartment of monocytes and macrophages. After phagocytosis, Nramp1 is targeted to the membrane of the microbe-containing phagosome, where it may modify the intraphagosomal milieu to affect microbial replication. Although the biochemical mechanism of action of Nramp1 at that site remains unknown, Nramp homologues have been identified in many other animal species and actually define a protein family conserved from bacteria to humans. Some of these homologues have been shown to be divalent cation transporters. Recently, a second member of the mammalian Nramp family, Nramp2, was discovered and shown to be mutated in animal models of iron deficiency. The Nramp2 protein was subsequently shown to be the major transferrin-independent iron uptake system of the intestine. Together, these results suggest that Nramp1 may control intracellular microbial replication by actively removing iron or other divalent cations from the phagosomal space.

The immunogenetics of human infectious diseases.

Twin and adoptee studies have indicated that host genetic factors are major determinants of susceptibility to infectious disease in humans. Twin studies have also found high heritabilities for many humoral and cellular immune responses to pathogen antigens, with most of the genetic component mapping outside of the major histocompatibility complex. Candidate gene studies have implicated several immunogenetic polymorphisms in human infectious diseases. HLA variation has been associated with susceptibility or resistance to malaria, tuberculosis, leprosy, AIDS, and hepatitis virus persistence. Variation in the tumor necrosis factor gene promoter has also been associated with several infectious diseases. Chemokine receptor polymorphism affects both susceptibility ot HIV-1 infection and the rate of progression to AIDS. Inactivating mutations of the gamma-interferon receptor lead to increased susceptibility to typical mycobacteria and disseminated BCG infection in homozygous children. The active form of vitamin D has immunomodulatory effects, and allelic variants of the vitamin D receptor appear to be associated with differential susceptibility to several infectious diseases. NRAMP1, a macrophage gene identified by positional cloning of its murine homologue, has been implicated in susceptibility to tuberculosis in Africans. Whole genome linkage analysis of multi-case families is now being used to map and identify new loci affecting susceptibility to infectious diseases. It is likely that susceptibility to most microorganisms is determined by a large number of polymorphic genes, and identification of these should provide insights into protective and pathogenic mechanisms in infectious diseases.

Current and future clinical applications of interferon-gamma in host antimicrobial defense.

The T cell-derived macrophage-activating lymphokine, interferon-gamma (IFN-gamma), is the most broadly acting antimicrobial-inducing and host defense-enhancing cytokine thus far identified in experimental models of infectious diseases. The activity induced by IFN-gamma encompasses all classes of non-viral pathogens including intracellular and extracellular parasites, fungi and bacteria. In man, treatment with immuno-enhancing doses of IFN-gamma is safe, well-tolerated and stimulates the antimicrobial mechanisms of blood monocytes, circulating neutrophils and tissue macrophages. Aerosol administration activates alveolar macrophages in a compartmentalized fashion. Monocytes from IFN-gamma-treated patients with cancer, leprosy, and AIDS all respond with the activated phenotype, and suppressed monocyte HLA-DR expression in trauma patients can be up-regulated by IFN-gamma therapy. Thus far, IFN-gamma has been recognized as effective in the prophylaxis of chronic granulomatous disease and as adjunctive treatment in at least one systemic intracellular infection, visceral leishmaniasis. Additional trials suggest beneficial effects as prophylaxis in trauma and as treatment in leprosy, cutaneous leishmaniasis, and HIV- and non-HIV-related disseminated atypical mycobacterial infection. IFN-gamma is also being tested as a prophylaxis in patients with burns and advanced HIV infection and as an adjunct in drug-resistant tuberculosis. Future antimicrobial applications for IFN-gamma include: a) long-term prophylaxis in T cell-deficient states, b) short-term prophylaxis in patients with a reversible host defense defect such as granulocytopenia or immune response suppression induced by trauma or burn injury, and c) adjunctive treatment along with conventional antibiotic therapy for i) nosocomial pneumonia (aerosol administration), ii) opportunistic infections in general, iii) infections which typically respond poorly to available treatment and iv) for infections which require prolonged therapy for cure. In the latter, the addition of IFN-gamma may accelerate the response to conventional therapy and permit a clinically important reduction in the duration of treatment while preserving efficacy.

Immunogenetics in the analysis of resistance to intracellular pathogens.

Recent studies have identified genes involved in resistance to intracellular pathogens. Such genes include the murine MHC class I gene, Ld (toxoplasmosis), HLA-BW53, HLA DRB1* 1302-DQ B10s01 and TNF2 (malaria), murine Nramp (toxoplasmosis, leishmaniasis and tuberculosis), gene(s) modulating the T-helper type 1 and type 2 dichotomy (leishmaniasis, leprosy and HIV infection) and the natural killer cell complex (cytomegalovirus infection). There also have been other advances in immunogenetics that have led to a better understanding of resistance to intracellular pathogens. These include effector mechanisms of immune response genes and factors modulating genetic susceptibility. Identification of genes that determine resistance/susceptibility (and their effector mechanisms) has impacted on vaccine development. Immunogenetics has been important in characterizing roles of TCR genes, superantigens, and host genes that play a role in molecular mimicry in disease pathogenesis. In addition, recent work with gene knockout, recombinant inbred or congenic, mutant, consomic, and transgenic mice, positional cloning, mouse/human gene homologies to identify candidate human resistance genes, and the rapid expansion of the gene transcription maps of the human genome, have been important in analysis of resistance to intracellular pathogens.

Interferon-gamma and host antimicrobial defense: current and future clinical applications.

In the 1980s, substantive experimental data and emerging clinical results suggested that interferon-gamma (IFN-gamma), a T-cell-derived lymphokine with broad macrophage-activating effects, had considerable potential in the treatment of nonviral infections as a host defense-enhancing antimicrobial agent. During the past 6 years, the breadth of the experimental activity with IFN-gamma against nonviral pathogens has been expanded still further, and pilot studies and formal clinical trials using IFN-gamma have been undertaken in the treatment of patients both at risk for and with active infections. Thus far, IFN-gamma has been approved for use as prophylaxis in patients with chronic granulomatous disease. However, IFN-gamma also appears effective as adjunctive therapy for at least one disseminated intracellular infection (visceral leishmaniasis), and in conjunction with conventional therapy, may benefit patients with certain forms of cutaneous leishmaniasis, disseminated Mycobacterium avium complex infection, and lepromatous leprosy. Despite a rationale for its use, IFN-gamma has not yet been tested in tuberculosis or fungal or common bacterial infections nor sufficiently examined in the prevention and/or treatment of the opportunistic infections related to acquired immunodeficiency syndrome. IFN-gamma remains a promising host defense-enhancing cytokine with still unexplored clinical potential.

Anticardiolipin antibodies in patients with infectious diseases.

IgG or IgM anticardiolipin antibodies were present in the sera of 67% of 33 patients with Hansen's disease, in 53% of 30 patients with tuberculosis and in 50% of 16 patients with endocarditis. Despite the high frequency of these antibodies, no patient had a history of thrombosis or abortion. Anti-denatured DNA antibodies were tested in patients with tuberculosis and patients with Hansen's disease. Only in the latter group did we observe a statistically significant association between anticardiolipin and anti-denatured DNA antibodies. Anticardiolipin binding activity, however, could not be inhibited by preincubation of sera with a variable concentration of denatured DNA. These data suggest that: a) Anticardiolipin antibodies in infectious diseases do not necessarily participate in the pathogenesis of thrombotic or obstetric complications; b) Anti-denatured DNA and anticardiolipin antibodies in the population studied do not have a cross-reaction.

Interferon-gamma, the activated macrophage, and host defense against microbial challenge.

Recent research on human macrophage activation has reemphasized the critical role of the lymphokine-secreting T cell in converting quiescent macrophages to efficient microbicidal phagocytes. Interferon-gamma, a key lymphokine secreted by antigen-triggered T4+ helper cells, is capable of inducing the macrophage to act against a diverse group of microbial targets, in particular, intracellular pathogens. In animal models, treatment with recombinant interferon-gamma is beneficial in systemic intracellular infections, and inhibition of endogenous interferon-gamma activity impairs host resistance. Trials in patients with cancer, leprosy, and the acquired immunodeficiency syndrome (AIDS) have shown that interferon-gamma can activate the mononuclear phagocyte in humans. This research and the identification of patients whose T cells fail to produce interferon-gamma properly has set the stage for evaluating the role of macrophage-activating immunotherapy using interferon-gamma in various human infectious diseases.

Interferon-gamma: involvement in human disease.

The susceptibility to infection in various situations is discussed, emphasizing the role of interferon-gamma as a vital mediator of host resistance.